Anti-proliferation evaluation of new derivatives of indole-6-carboxylate ester as receptor tyrosine kinase inhibitors

Aim: The main goal was to create two new groups of indole derivatives, hydrazine-1-carbothioamide (4a and 4b) and oxadiazole (5, and 6a–e) that target EGFR (4a, 4b, 5) or VEGFR-2 (6a–e). Materials & methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR/VEGFR-2, and the anti-proliferative properties were tested in vitro. Results: Compounds 4a (targeting EGFR) and 6c (targeting VEGFR-2) were the most effective cytotoxic agents, arresting cancer cells in the G2/M phase and inducing the extrinsic apoptosis pathway. Conclusion: The results of this study show that compounds 4a and 6c are promising cytotoxic compounds that inhibit the tyrosine kinase activity of EGFR and VEGFR-2, respectively.
Two hydrazine-1-carbothioamide derivatives (4a and 4b), and oxadiazole-2-thione compound (5) were designed and synthesized to mimic the pharmacophoric properties of EGFR tyrosine kinase inhibitors.
Several oxadiazole derivatives (6a–e) were designed and synthesized to mimic the pharmacophoric properties of VEGFR-2 tyrosine kinase inhibitors.
Molecular docking revealed that compounds 4a and 6c were the best fits within the active sites of EGFR and VEGFR-2 tyrosine kinases, respectively.
IC50 values against HepG2, HCT-116 and A549 cancer cell lines were calculated.
Compounds 4a and 6c were noted to be the most potent anti-proliferative compounds against cancer cells.
Compound 4a with an unsubstituted phenyl moiety (R=H) exhibited the highest EGFR enzyme inhibitory activity. Compound 6c with a chloro group at the 4-position of the aromatic ring showed the highest VEGFR-2 enzyme inhibitory activity.